Key Takeaways:
- Zerlasiran, a short interfering RNA (siRNA) targeting lipoprotein(a) (Lp(a)), was well tolerated and led to significant reductions in Lp(a) serum concentrations in both healthy participants and patients with stable atherosclerotic cardiovascular disease (ASCVD).
- A single dose of 600 mg of zerlasiran resulted in a maximal median reduction of Lp(a) by 99%, with 90% and 89% reductions sustained at 201 days for the 300 mg and 450 mg doses, respectively.
- The study found no serious adverse events, with mild to moderate injection site reactions being the most common side effect. Elevations in C-reactive protein were transient and resolved by day 7.
Zerlasiran, a short interfering RNA (siRNA) therapy targeting lipoprotein(a), demonstrated significant reductions in serum concentrations of lipoprotein(a) in a randomized phase 1 trial. Lipoprotein(a) is a recognized causal factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, yet no pharmacological treatments for its reduction are currently approved. The ALPACAR phase 2 trial (ClinicalTrials.gov identifier NCT04606602) investigated the safety, tolerability, and efficacy of zerlasiran in healthy participants and patients with stable ASCVD and elevated lipoprotein(a) concentrations (≥150 nmol/L). The results of this trial were presented at AHA 2024 with simultaneous publication in JAMA.
The trial, conducted across seven international research sites, enrolled 32 participants in a single-dose phase and 36 patients in a multiple-dose phase. Participants were randomized to receive varying subcutaneously delivered doses of zerlasiran or placebo. The safety profile of zerlasiran was favorable, with no serious adverse events reported. Injection site reactions, the most common side effect, were mild to moderate. Temporary increases in C-reactive protein levels were observed but normalized within seven days. There were no incidents of liver toxicity or clinically significant prolongation of the QT interval.
Among 178 patients, mean (SD) age was 63.7 (9.4) years, 46 (25.8%) were female, with a median (IQR) baseline lipoprotein(a) concentration of 213 (177-282) nmol/L; 172 patients completed the trial. In the single-dose arm, lipoprotein(a) levels were reduced by a median of 30% (IQR, −51% to −18%) for the 300 mg dose and 29% (IQR, −39% to −7%) for the 600 mg dose after 365 days whereas the placebo group saw a median increased lipoprotein(a) level of 14% (IQR, 13%, 15%). In the multiple-dose arm, maximal median reductions in lipoprotein(a) levels were 97% (IQR, −98% to −95%) for the 200 mg group, 98% (IQR, −99% to −97%) for the 300 mg group, and 99% (IQR, −99% to −98%) for the 450 mg group, with sustained reductions of 60%, 90%, and 89% at 201 days, respectively. In comparison, the placebo group had a reduction of 0.3% at 201 days.
Dr. Steven Nissen, lead investigator, emphasized the importance of these findings: “The observed reductions in lipoprotein(a) levels with zerlasiran highlight its potential for managing a key cardiovascular risk factor. These findings support further development of serlasiran in phase 3 clinical trials.” These findings contribute to the growing body of evidence supporting RNA-based therapies as a promising strategy in lipid management.